Pathogens can avoid T-cell immunity by dampening the function of DCs [41, 42], which are professional antigen-presenting cells that sense pathogens through the engagement of pattern recognition receptors. Pathogen encounter generally leads to DC maturation and the secretion of immune-stimulating cytokines that contribute to the activation and polarization of T cells [43-45]. Upon exposure to RSV, most human and murine DCs display abortive levels of viral RNA synthesis, and only a fraction of cells become readily infected (Figure 2) [46-50]. Consistently, only negligible numbers of viral particles can be recovered from the supernatants of infected DCs. Thus, evidence suggests that these cells may be exploited by RSV to manipulate immunity rather than for viral replication. In fact, although DCs can recognize RSV molecular patterns via a variety of receptors, such as TLRs and RIG-1 [43, 44], human and murine DCs undergo only weak maturation after virus encounter. Thus, only a modest upregulation of surface activation markers, such as CD40, CD80, CD86 and MHC (Figure 2) [46-49, 51], is observed for DCs after RSV challenge. Nevertheless, DCs respond to the virus by secreting polarizing cytokines, such as IL-6 and IL-10, which can promote T-cell differentiation into phenotypes that are poorly effective at clearing the virus (Figure 2) [47, 51]. Therefore, RSV seems to have developed molecular strategies to interfere with the function of DCs. Accumulating data suggest that in vitro infected human and murine DCs fail to efficiently prime T cells [47-49, 52], probably because of the reduced capacity of RSV-infected DCs to secrete activating cytokines, such as IL-12, required to induce CD4+ T cells capable of driving the expansion of cytotoxic and memory CD8+ T cells (Figure 2) [22, 38, 46, 47, 49, 53, 54]. However, the identification of host and viral molecular determinants that account for the altered response shown by DCs to RSV infection remains elusive. Along these lines, a recent report showed that neonate and adult human DCs secrete different cytokine patterns in response to RSV, especially for the levels of TGF-β produced . Cord blood-derived DCs secreted significantly more TGF-β1 in response to RSV infection than did DCs obtained from adult blood . Furthermore, contrastingly different cytokine profiles were obtained in the co-cultures of these RSV-infected DCs with autologous T cells. Whereas co-cultures with adult DCs contained IL-2, IL-12, IFN-γ and TNF-α, those with cord DCs contained IL-1β, IL-4, IL-6 and IL-17 . This differential response of neonatal and adult DCs to RSV could contribute to increased infant susceptibility to developing inadequate virus-specific T-cell immunity and lung pathology. Consistent with this notion, neutralization of IL-17 in RSV-infected mice was recently shown to significantly reduce the production of mucus in the airways and decrease viral loads in the lungs . Furthermore, IL-17 neutralization led to an increase in the number of RSV-specific CD8+ T cells, thereby reducing the production of Th2 cytokines in RSV-exacerbated allergic mice. In another study, IL-4−/− mice displayed reduced peribronchial lymphocytic inflammation as well as increased levels of the Th1 cytokine IFN-γ . RSV infection leads to a sustained increase in the lung recruitment of both myeloid (mDCs) and plasmacytoid DCs (pDCs) in mice and humans. Further, as a result of infection, migration of these cells to the lymph nodes also takes place [58-62].
Figure 2. Respiratory syncytial virus (RSV) interferes with DC and T-cell function. (1) RSV can infect DCs, as shown by the surface expression of viral encoded proteins, such as the fusion F protein and intracellular expression of viral RNA (nucleocapsid gene). (2) Upon infection with RSV, DCs mature as a result of the engagement of surface and internal pathogen recognition receptors, such as TLRs, lectins and RIG-I by viral determinants. (3) RSV-infected DCs secrete cytokines that can either promote CD4+ T-cell differentiation into Th2 phenotypes (e.g. IL-10 and IL-6) or inhibit their function (e.g. IFN-λ and IFN-α) [49, 53]. Furthermore, infection in neonates may promote the generation of detrimental CD8+ T cells. Additionally, DCs can secrete chemokines, such as CXCL10 and CCL2, that modulate immune cell migration. (4) RSV can impair DC–T cell interaction by interfering with immunological synapse assembly (detailed in Figure 3). (5) The soluble form of the RSV G glycoprotein can interfere with T-cell differentiation and migration by interacting with CX3CR1 receptors expressed on the surface of T cells. (6) Few reports have provided evidence for direct interaction between RSV and T cells at their surface, which has been described to interfere with T-cell cytoskeleton organization in response to activating stimuli. (7) RSV can impair T-cell activation and function in the lungs by reducing IFN-γ secretion. (8) T cells activated in the context of an RSV infection can display Th2 phenotypes and secrete characteristic inflammatory cytokines
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Plasmacytoid DCs accumulating in the lungs of RSV-infected mice secrete IFN-α and other type-I IFNs in response to the virus and are thought to contribute to controlling RSV-mediated lung pathology [59, 63, 64]. On the other hand, DCs subtypes different from plasmacytoid, such as monocyte-derived human DCs, fail to secrete these cytokines in high amounts in response to RSV, which would partly reduce DC maturation . Previous experiments performed on human epithelial cell lines have reported that NS1/2 can interfere with STAT-2 function to modulate NF-κB and IRF-3 activity, leading to altered type-I IFN signalling [66, 67]. A recent report showed that RSV can also interfere with STAT-1 and STAT-2 signalling in murine bone-marrow derived DCs . In fact, NS1 could negatively modulate the capacity of human DCs to activate both CD4+ and CD8+ T cells by decreasing the proliferation of cytotoxic CD8+ T cells that migrate to the lungs and reducing the activation and proliferation of CD4+ Th17 cells with potential antiviral effects . Furthermore, NS1 was seen to promote the capacity of DCs to activate IL-4-secreting CD4+ T cells while reducing the proliferation of total CD4+ T cells. Strikingly, nearly all these effects were shown to be independent of type-I IFN signalling.
Blockade of the chemokine CCL20 during RSV infection in mice reduced the frequency of mDCs in the lungs but did not alter pDC numbers or the recruitment of T cells . Such a treatment ultimately led to reduced lung pathology and an enhanced Th1 effector response against RSV . Similar data were obtained in CCR6−/− animals, which support the notion that pDCs contribute positively to RSV clearance and that CCL20 may enhance this process [59, 69].